Chapter 13

CONTRIBUTING CAUSE

Inflammation

Inflammation plays an important role in metabolism, mitochondrial function, mental health, and metabolic health. Therefore, it plays an important role in the theory of brain energy.

Let’s start with an overarching observation—many people think of inflammation as a bad thing. Low-grade inflammation is often found in people with metabolic and mental disorders. Many speculate that neuroinflammation might be the root cause of at least some mental and neurological disorders. Cytokine storms (an overactive inflammatory response) can kill people with COVID. Lingering inflammation is one of the primary suspects for the cause of long COVID, in which people have mental and neurological symptoms for months or years after infection. Autoimmune disorders are when inflammation and the immune system are attacking a person’s own body. A “leaky gut” can cause chronic inflammation. For all these reasons, we have heard that inflammation causes much of what ails us. We are told to decrease inflammation.

However, inflammation isn’t always bad. It occurs all the time. It’s usually a normal process that plays countless beneficial roles in the human body. It is involved in fighting off infections and healing injuries. It serves important signaling functions. It is involved in the normal stress response. Inflammatory cytokines are a way to send stress signals throughout the body and brain. Microglial cells, the brain’s immune cells, play a role in brain development, learning, and memory. Without inflammation, we would die.

Inflammation, Metabolism, and Mental States

Inflammation is one way that the body allocates and uses metabolic resources, thereby directly affecting metabolism.

When inflammatory cytokines get released, more blood flows to that area of the body, bringing with it oxygen, glucose, amino acids, and fats to be used in some way. The inflammation is “calling” for these resources, and the body is allocating energy and supplies. This can occur due to infections or injuries, or in response to old or dying cells.

Inflammation can trigger the production of more immune cells and antibodies. These can be lifesaving when fighting off viruses, bacteria, and even newly formed cancer cells, but it takes energy and resources to make these. The body prioritizes dealing with these situations as they threaten the survival of the organism. Other times, the body is allocating resources to make adaptive changes, such as increasing the size of muscles after a workout or directing metabolic resources to specific brain regions for new learning. Even in these situations, inflammation is calling resources to these sites. In all these scenarios, there are fewer metabolic resources available to all the other cells in the body. In other words, inflammation takes a toll—a metabolic toll.

High levels of inflammation can change emotions, thoughts, motivations, and behaviors. For example, when people have a viral infection or cancer, the high levels of inflammation cause mental changes as well. People become lethargic, withdrawn, unmotivated, less confident, and more likely to want to climb into bed and rest. These are all adaptive. They are normal and healthy, even though they make people feel miserable. These changes allow for the conservation of metabolic resources. The body is fighting for its survival. This is no time to go out playing, exercising, or even reproducing. All available resources need to be used for survival. Some researchers have called this conservation-withdrawal behavior and have used these observations to better understand some of the symptoms of depression.

But it can go in the other direction, too. Mental states can cause inflammation. One fascinating study looked at humans and monkeys who were lonely and found that loneliness increased the stress response and induced a specific pattern of immune cell activation.¹ This left the lonely people and monkeys with chronic, low-grade inflammation. They were also more vulnerable to getting a viral infection. The researchers went so far as to infect the monkeys with a virus, and sure enough, the lonely monkeys had an impaired immune response. This helps explain why a mental symptom like loneliness has been linked to higher rates of not just mental disorders but also cardiovascular disease, Alzheimer’s disease, and premature death.²

When inflammation occurs for a prolonged period, or when it is extreme, the metabolic toll can trigger or exacerbate mental and metabolic disorders. When infections, allergies, cancers, and autoimmune disorders flare up, there can be an increase in new-onset mental disorders or an exacerbation of mental symptoms in people with existing disorders. To give one surprising example, people with runny noses (rhinitis) from something like hay fever are 86 percent more likely to develop depression.³ These inflammatory conditions are also well-known causes of delirium in the elderly. Likewise, there can be an increase in the symptoms of metabolic disorders. Blood sugar goes up in people with diabetes. People with cardiovascular disease can see an increase in blood pressure, experience chest pain, or suffer another heart attack.

A large population study of more than one million children in Denmark found that children hospitalized for serious infections were 84 percent more likely to develop a subsequent mental disorder and 42 percent more likely to be prescribed a psychiatric medication.⁴ The biggest risk was within three months of the infection. In teens, there was an eightfold increase in OCD. In case you’re thinking that all the kids were just “anxious” because they got hospitalized, the most common diagnoses included schizophrenia, OCD, personality disorders, mental retardation, autism, ADHD, oppositional defiant disorder, conduct disorder, and tic disorders. These are serious brain disorders, not just “anxiety” due to a hospitalization. And as you’ll note, the diagnoses are widespread, not specific to any one disorder, which is consistent with the brain energy theory.

These are just a couple of examples of the research demonstrating that inflammatory conditions can lead to the development or exacerbation of both mental and metabolic disorders. But is there evidence that mitochondria are involved?

Inflammation and Mitochondria

Inflammation and mitochondria are in a complex feedback loop. Mitochondria are involved in many aspects of the normal inflammatory response, turning it both on and off. Inflammation, in turn, can impair mitochondrial function. Furthermore, mitochondrial dysfunction, even from other causes, can lead to inflammation. It’s all a vicious cycle. I’ll walk you through some of the evidence supporting this.

Mitochondria play a role in normal inflammation. In the chapter on mitochondria, I already shared with you the study demonstrating that they are responsible for the different phases of wound healing in macrophages. One scientific article, “Mitochondria in Innate Immune Responses,” reviewed the many complex ways in which mitochondria are directly or indirectly involved in many aspects of the immune response, including fighting viruses and bacteria, but also playing a role in cell damage and stress.⁵ Another paper published in Cell found that mitochondria appear to play a role in immune cell death when the time comes to turn off the immune response.⁶ If mitochondria are not functioning properly in these cells, there will be problems with inflammation and immune cell function. It can lead to either an overactive or underactive immune and inflammatory response. These have been observed in many mental and metabolic disorders.

Inflammation directly impacts the function of mitochondria. For example, tumor necrosis factor (TNF), an inflammatory cytokine, has been found to directly inhibit mitochondrial function.⁷ A more important example is that of interferon, another inflammatory cytokine. Its production is strongly influenced by mitochondria, but it has also been shown to directly inhibit three mitochondrial genes, resulting in changes in mitochondrial function.⁸ Furthermore, interferon has been shown to directly suppress mitochondrial ATP production in some brain cells.⁹ What makes this such an important example is that interferon can be given to people as a medication when treating serious infections or cancers. Shortly after starting interferon, all hell can break loose in terms of psychiatric symptoms—essentially, anything goes. The list includes depression, fatigue, irritability, insomnia, suicidal behavior, manic symptoms, anxiety, psychotic symptoms, concentration difficulties, and delirium.¹⁰ All existing mental disorders can get worse with interferon. So here we go again. One drug, interferon, can produce every symptom known to psychiatry. Why? Mitochondria.

There are numerous other ways in which inflammation, immune cells, and cytokines can impact mitochondrial function, but for our purposes, the bottom line is that inflammation can cause mitochondrial dysfunction.

Inflammation can also affect brain development. In a fetus or young child, the brain can develop abnormally due to inflammatory conditions. For example, pregnant women with infections are 80 percent more likely to have a child with autism.¹¹ There are many animal models of autism in which researchers inject inflammatory molecules into pregnant mice in order to induce autism in the offspring. How can we tie this all together? Mitochondria.

Inflammation can also be a consequence of mitochondrial dysfunction. In addition to mitochondrial dysfunction in immune cells directly impacting the inflammatory and immune response, if mitochondria in other types of cells aren’t functioning properly, that can also lead to the chronic, low-grade inflammation that we see in many people with metabolic and mental disorders.

Cells that are metabolically compromised can fall into a state of disrepair. They can have maintenance problems, shrink, or die. They can have high levels of oxidative stress. All of this triggers inflammation. The cells send out signals, damage-associated molecular patterns (DAMPs), that they are in need of repair. Dead cells need to be disposed of properly. Inflammation serves these purposes. In fact, mitochondria themselves, or at least parts of them, are known to be powerful DAMPs. When they are released from a struggling cell, it triggers inflammation. Inflammation in these cases is a normal response; it’s not the primary problem, but instead a symptom of a metabolic problem. Interfering with it likely won’t change a thing. In fact, in some cases, it might make things worse, as it can interfere with the normal healing process. The low-grade inflammation associated with all the mental and metabolic disorders is likely a consequence of widespread metabolic dysfunction. To address the problem, we need to understand what is causing the metabolic problems in the first place. This can include a wide variety of factors, like a poor diet, stress, hormonal problems, a lack of sleep, heavy use of alcohol or drugs, and other toxins. You’ll hear more about some of these soon enough. In order to address the problem, we must address the metabolic dysfunction in the cells. If we can restore metabolic health, the inflammation will stop.

The Role of Inflammation in Treatment

For decades, suppressing inflammation has been an area of great interest to researchers. They have been studying antioxidants and anti-inflammatory agents for both metabolic and mental disorders. Billions of dollars have been spent on this research. The list of agents includes things like vitamin E, omega-3 fatty acids, N-acetylcysteine, and nonsteroidal anti-inflammatory medications like ibuprofen. When all is said and done, they don’t appear to be all that effective as treatments. Their use in depression, schizophrenia, Alzheimer’s disease, cardiovascular disease, obesity, and diabetes has been disappointing, at best, even though all these disorders have been associated with higher levels of chronic inflammation. One meta-analysis showed slight benefits for some of these agents for some mental disorders, but the improvements were minimal and usually not clinically meaningful.¹² On top of that, given that inflammation plays a role in normal brain and body functions, it’s possible that suppressing it with medications may have unintended adverse consequences over the long run.

So, does inflammation matter in treatment? It does.

First, there are many lifestyle factors that I already mentioned that can cause widespread metabolic dysfunction, which can then lead to chronic inflammation. Addressing these can play a powerful role in decreasing inflammation and addressing metabolic and mental disorders. Taking an antioxidant to counteract the negative effects of these lifestyle factors simply doesn’t work.

Autoimmune disorders are associated with high levels of inflammation and play a role in mental and metabolic disorders. Addressing these is important. Sometimes, it might require anti-inflammatory treatments. In other cases, it might require addressing hormone deficiencies. You’ll need to work with your healthcare provider on all of this.

Chronic infections can also be a serious problem. When the body is unable to eliminate a viral or bacterial infection, it takes a metabolic toll and can lead to problems. HIV, chronic Lyme disease, hepatitis, and others can play a role in metabolic and mental health. You’ll need to work with your healthcare provider to address these with optimal care.

Allergies can also lead to chronic inflammation. Sometimes, allergens can be avoided, but other times, you may need to work with your healthcare provider to select appropriate treatments.

Dental hygiene can also affect inflammation, and in turn, can impact both metabolic and mental disorders. It’s important to brush and floss your teeth regularly and get regular dental checkups. This is one way to reduce a source of inflammation in your body.

Summing Up